Browsing by Subject "PD-L1"

Now showing 1 - 5 of 5
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    ItemOpen Access
    A meta-analysis with systematic review: Efficacy and safety of immune checkpoint inhibitors in patients with advanced gastric cancer.
    (Frontiers in oncology, 2022-01) El Helali, Aya; Tao, Jun; Wong, Charlene HL; Chan, Wendy Wing-Lok; Mok, Ka-Chun; Wu, Wing Fong; Shitara, Kohei; Mohler, Markus; Boku, Narikazu; Pang, Herbert; Lam, Ka On

    Background

    While the efficacy of immune checkpoint inhibitors (ICIs) is increasingly recognized in advanced gastric cancer (aGC), overall survival (OS) has not been consistently improved across the different randomized controlled trials (RCTs). This meta-analysis aimed to quantify the efficacy and safety of ICI and explore potential predictive tumor tissue biomarkers in aGC.

    Methods

    A random-effect pairwise meta-analysis was used to evaluate the primary outcome of OS. Sensitivity analysis was performed to investigate the effects of ICIs on PD-L1 status, TMB, MSI-H, and the Asian patient population. We extracted the OS Kaplan-Meier curves from the included trials to compare the effect of PD-L1 status on response to ICIs using DigitizeIt 2.5 and Guyot's algorithm.

    Results

    A pairwise meta-analysis of seven RCTs included in this study showed that ICIs were more effective than the comparator in improving OS (pooled HR: 0.84). We demonstrated that PD-1 ICIs were additive when combined with the comparator arm (pooled HR: 0.79). A sensitivity analysis showed that PD-1 ICIs were associated with better OS outcomes in the Asian patient population as monotherapy (pooled HR: 0.66) or in combination with chemotherapy (pooled HR: 0.83). We demonstrated that tumors with PD-L1 ≥1 (P = 0.02) and PD-L1 ≥10 (P = 0.006) derived OS benefit from ICI monotherapy. Equally, MSI-H (P <0.00001) and TMB-high (P <0.0001) tumors derived favorable survival benefits from ICIs.

    Conclusions and relevance

    The results of this meta-analysis suggest that ICIs result in improved OS outcomes in aGC. The benefits varied with different ethnicities, class of ICI, PD-L1 expression, MSI status, and TMB.

    Systematic review registration

    https://www.crd.york.ac.uk/prospero, identifier (CRD42019137829).
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    Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond.
    (J Immunother Cancer, 2018-01-25) Zhu, Jason; Armstrong, Andrew J; Friedlander, Terence W; Kim, Won; Pal, Sumanta K; George, Daniel J; Zhang, Tian
    Immune checkpoint inhibitors targeting the PD-1 pathway have greatly changed clinical management of metastatic urothelial carcinoma and metastatic renal cell carcinoma. However, response rates are low, and biomarkers are needed to predict for treatment response. Immunohistochemical quantification of PD-L1 was developed as a promising biomarker in early clinical trials, but many shortcomings of the four different assays (different antibodies, disparate cellular populations, and different thresholds of positivity) have limited its clinical utility. Further limitations include the use of archival specimens to measure this dynamic biomarker. Indeed, until PD-L1 testing is standardized and can consistently predict treatment outcome, the currently available PD-L1 assays are not clinically useful in urothelial and renal cell carcinoma. Other more promising biomarkers include tumor mutational burden, profiles of tumor infiltrating lymphocytes, molecular subtypes, and PD-L2. Potentially, a composite biomarker may be best but will need prospective testing to validate such a biomarker.
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    First-line treatment of metastatic melanoma: role of nivolumab.
    (Immunotargets Ther, 2017) Force, Jeremy; Salama, April Ks
    Historically, the median overall survival of metastatic melanoma patients was less than 1 year and long-term survivors were rare. Recent advances in therapies have dramatically shifted this landscape with increased survival rates and the real possibility that long-term disease control is achievable. Advances in immune modulators, including cytotoxic T-lymphocyte antigen-4 and programmed death-1 based treatments, have been an integral part of this success. In this article, we review previous and recent therapeutic developments for metastatic melanoma patients. We discuss advances in immunotherapy while focusing on the use of nivolumab alone and in combination with other agents, including ipilimumab in advanced melanoma. One major goal in melanoma research is to optimize combination strategies allowing for more patients to experience benefit while minimizing toxicity. A better understanding of the optimal sequencing, combinations, and mechanisms underlying the development of resistance may provide evidence for rational clinical trial designs of novel immunotherapy strategies in melanoma and other cancer subtypes.
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    Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors.
    (Rheumatology (Oxford, England), 2019-12) Weinmann, Sophia C; Pisetsky, David S
    Immune checkpoint inhibitors are novel biologic agents to treat cancer by inhibiting the regulatory interactions that limit T cell cytotoxicity to tumours. Current agents target either CTLA-4 or the PD-1/PD-L1 axis. Because checkpoints may also regulate autoreactivity, immune checkpoint inhibitor therapy is complicated by side effects known as immune-related adverse events (irAEs). The aim of this article is to review the mechanisms of these events. irAEs can involve different tissues and include arthritis and other rheumatic manifestations. The frequency of irAEs is related to the checkpoint inhibited, with the combination of agents more toxic. Because of their severity, irAEs can limit therapy and require immunosuppressive treatment. The mechanisms leading to irAEs are likely similar to those promoting anti-tumour responses and involve expansion of the T cell repertoire; furthermore, immune checkpoint inhibitors can affect B cell responses and induce autoantibody production. Better understanding of the mechanisms of irAEs will be important to improve patient outcome as well as quality of life during treatment.
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    PD-L1/PD-1 Biomarker for Metastatic Urothelial Cancer that Progress Post-platinum Therapy: A Systematic Review and Meta-analysis.
    (Bladder cancer (Amsterdam, Netherlands), 2019-11-22) Tan, Wei Phin; Tan, Wei Shen; Inman, Brant A

    Background

    Immune checkpoint inhibitors (ICI) are extremely expensive and most patients with metastatic urothelial carcinoma (mUC) do not benefit significantly from their use.

    Objective

    We performed a systematic review and meta-analysis to determine response rates and survival outcomes on patients with mUC progressing despite prior platinum-based chemotherapy receiving ICI stratified by biomarker status.

    Methods

    We performed a comprehensive literature search for all articles in PubMed and Embase up to 06/15/2019 to identify all studies pertaining to programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) receptor targeted therapies for mUC that reported biomarkers. Given that biomarkers are reported on different scales and with different metrics, we defined each biomarker as either positive or negative using the definitions implemented in each individual trial. We meta-analyzed the data, reconstructed overall (OS) and progression-free survival (PFS) curves, and analyzed response rates by biomarker status. OS and PFS were analyzed in a pooled Kaplan-Meier analysis and pseudo-individualized patient data (IPD) extracted.

    Results

    We identified 1429 manuscripts of which 8 met inclusion criteria, with a total of 1837 treated patients with outcomes data. On proportional hazards survival analysis, patients in the biomarker negative group were associated with a lower PFS (HR 1.48, 95% CI: 1.18 - 1.85, p < 0.001) and lower OS (HR 1.54, 95% CI: 1.32 - 1.80, p < 0.001) when compared to the biomarker positive group. Response data was available for 1641 patients and random effects proportion show complete response in 8% and 3% in biomarker positive and negative patients, respectively.

    Conclusions

    ICI therapy for metastatic UC post platinum therapy has a higher overall response rate, OS and PFS in patients who are biomarker positive compared to those who are negative. However, some patients who are biomarker negative do achieve complete responses. A better biomarker for patient selection is essential before biomarkers can be used to stratify candidates for ICI therapy.